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Stroke and Neuroprotection

Stroke and neuroprotection

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Page 1: Stroke and neuroprotection

Stroke and Neuroprotection

Page 2: Stroke and neuroprotection

Stroke: Definition

  A syndrome characterized by acute onset of a neurologic

deficit that persists for at least 24 hours, reflects focal

involvement of the central nervous system, and is the result

of a disturbance of the cerebral circulation.

Page 3: Stroke and neuroprotection

Stroke : A silent epidemic

• Stroke the second leading cause of death and major cause of

disability worldwide1,2

• Two-thirds of stroke deaths occur in developing countries1,2

• In India, the incidence and 30 day case fatality rates are

higher than that in developed countries3,4

• Significant increase in noncommunicable diseases such as

stroke and CAD in both urban and rural India2

1. .Donnan GA, Fisher M, et al, Lancet 2008;371:1612-232. .Pandian JD, Srikanth V, et al, Stroke 2007;38:3063-93. .Das K, Banerjee TK, et al, Stroke 2007;38:906-104. .Dalal P, Bhattacharjee M, et al, Indian Acad Nerolol 2007;10:130-6

Page 4: Stroke and neuroprotection

Stroke in India

• During the last decade, the age-adjusted prevalence rate of

stroke was between 250-350/100,000.

• Recent studies showed that the age-adjusted annual

incidence rate was 105/100,000 in the urban community of

Kolkata and 262/100,000 in a rural community of Bengal.

• The ratio of cerebral infarct to hemorrhage was 2.21.

• Hypertension was the most important risk factor.

• Stroke represented 1.2% of total deaths in India.

Epidemiology of stroke in India, Tapas KumarNeurology Asia 2006; 11 : 1 – 4

Page 5: Stroke and neuroprotection

Stroke types and incidence:

Page 6: Stroke and neuroprotection

National Stroke Association developed

the following guidelines to help people reduce their risk for stroke…

Up to 80% of strokes are preventable!Up to 80% of strokes are preventable!

Page 7: Stroke and neuroprotection

Etiology

• Complication of several disorders

• Atherosclerosis – most common.

• Hypertension, smoking, diabetes.

• Heart disease – Atrial fibrillation.

• Other: – Trauma – fat embolism

– Tumor, Infection

Page 8: Stroke and neuroprotection

Risk Factors

• Heart disease

• Arrhythmias

• Diabetes Mellitus

• Smoking

• Obesity

• Transient ischemic attacks (TIA’s)

Page 9: Stroke and neuroprotection

Ischaemic cascade

Ischaemic brain injury results from a cascade

Starts with energy depletion leading to cell death

Reduced blood supply causes starving of neurons

Failure of mitochondria to produce ATP

ATP dependent ion channels stop functioning

Neurons depolarize,allowing excess entry of calcium and

sodium

Excess glutamate release from synaptic terminals

Pathophysiology - Stroke

Page 10: Stroke and neuroprotection

Excess glutamate causes neurotoxicity

Release of inflammatory substances from clot causes cell membrane damage

Free radicals produced by membrane lipid degradation and mitochondrial injury

Free radicals cause destruction of cell membrane & other vital functions of cell

Pathophysiology- Stroke

Page 11: Stroke and neuroprotection

Pathophysiology- stroke

Page 12: Stroke and neuroprotection

Neurons in the penumbra may

benefit from neuroprotection

before and after reperfusion

Reperfusion-induced oxidative stress is accompanied by deterioration of brainMitochondria1

Mediators of inflammation, cytokines, such as platelet-activating factor, interleukin-1(IL-1), and tumor necrosis factor β, are produced by injured brain cells2

Nitric oxide and oxidative stress are linked to DNA damage and activation of poly(ADPribose) polymerase, a nuclear enzyme that facilitates DNA repair and regulates transcription3

Pathophysiology

1. Schild L, FEBS J. 2005;272(14):3593-601. 2. Dirnagl U, Trends Neurosci. 1999;22(9):391-7.3. Lo EH, Nat Rev Neurosci. 2003;4(5):399-415.

Page 13: Stroke and neuroprotection

• Cell damage leads to cell death

There is evidence that free radicals

and peroxynitrate can cause cell

damage1

• The important role of oxygen

freeradicals in cell damage

associated with stroke is

underscored by the fact that even

delayed treatment with free-radical

scavengers can be effective in

experimental focal cerebral

ischemia2

• In milder ischemic injury, cell death

resembles apoptosis (cell suicide),

particularly within the ischemic1. Lipton P. Ischemic cell death in brain neurons. Physiological Reviews. Oct 1999;vol. 79; 1431-1568. 2. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke:an integrated view. Trends Neurosci. 1999;22(9):391-7.

Pathophysiology

Page 14: Stroke and neuroprotection

Immediate Treatment Options

Thrombolysis (tPA) Aspirin Antiplatelet agents Fluids “Blood Thinner” (heparin) Neuroprotection: new option

Page 15: Stroke and neuroprotection

Management of ischaemic stroke

• Stroke treatment shown rapid advances over last decade or so

• Proven therapies include IV thrombolytics, use of aspirin within 48 hrs and decompressive surgery for malignant MCA infarction1

• Secondary prevention measures include antiplatelets, anticoagulants, cholesterol reduction1

1. .Donnan GA, Fisher M, et al, Lancet 2008;371:1612-232. Brainin M, Teuschl Y, et al, Lancet Neurol 2007;6:533-61,

Rapid diagnosis, implementation of early preventive treatment, early recognition of

complications and mobilization improve overall outcomes2

Page 16: Stroke and neuroprotection

• Intravenous thrombolysis with rtPA within 3 hrs of symptom onset, currently approved for management of acute ischaemic stroke

• It improves rates of favorable outcome

• Patients with mild to moderate strokes, younger persons and those treated very early have best chances for favourable outcome

P. N. Sylaja,Ann Indian Acad Neurol 2008;11:S24-S29

Intravenous thrombolysisA Potent Weapon

Page 17: Stroke and neuroprotection

• Small percentage of patients receive rtPA

• Narrow inclusion criteria within 3 hrs and multiple exclusion limits the use of rtPA

• IV rtPA given alone produces recanalization in about 50% of patients*

• Major hindrance to thrombolytic therapy is delay in patients reaching hospital

• Healthcare infrastructure poor in rural areas

• Access to and affordability of investigation and treatment are major concern

Intravenous thrombolysisLimitations

P. N. Sylaja,Ann Indian Acad Neurol 2008;11:S24-S29* - Jose Suarez, Ann Indian Acad Neurol 2008;11:S30-38

Page 18: Stroke and neuroprotection

• Alternative approaches to IV thrombolytic administration have been explored

• IA rtPA or streptokinase or a combination of IV rtPA within 3 hrs and followed by IA rtPA are being used

• Therapeutic time window is expanded

• However, time to treatment for IA thrombolysis is longer compared to IV

• Limitations: Need to assemble angiography team, confirm occlusion, risk of invasive technique and also cost of treatment

Intra-arterial thrombolysisAlternative/ Additional approach

Jose Suarez, Ann Indian Acad Neurol 2008;11:S30-38

Page 19: Stroke and neuroprotection

• Patients with large cortical or cerebellar infarctions are at high risk of developing malignant cytotoxic edema

• Peak of brain edema typically occurs at day 2 to 7, but can occur as late as day 14

• Medical treatment includes mannitol or hypertonic saline• However, the anti-edematous effect of these agents are based

on osmosis principle only

Infarct related edema

David S, Stephan M, Clin Chest Med 30 (2009) 103-122

Page 20: Stroke and neuroprotection

Neuroprotection in Stroke

Page 21: Stroke and neuroprotection

Neuroprotection

• Neuroprotection is the mechanisms and strategies used to protect against neuronal injury or degeneration in the Central Nervous System (CNS) following acute disorders (e.g. stroke or nervous system injury/trauma) or as a result of chronic neurodegenerative diseases (e.g. Parkinson's, Alzheimer's, Multiple Sclerosis).

Page 22: Stroke and neuroprotection

ISCHEMIC PENUMBRA

• In the area of ischemia, there is a CENTRAL CORE with marked reduction in CBF and a surrounding area of marginal blood flow called the ‘ISCHEMIC PENUMBRA’.

• Ischaemic penumbra is “ischaemic tissue which is functionally impaired and is at risk of infarction and has the potential to be salvaged by reperfusion and/or other strategies.

• The ischemic area becomes perfusion dependent and any decrease in systemic blood pressure can extend the area of ischemia and infarction. In the penumbra, there is a moderate ischemia.

CORE ISCHEMIC AREA (CBF<25% OF NORMAL

PENUMBRA (CBF ~ 25 – 50% OF NORMAL)

Page 23: Stroke and neuroprotection

The penumbral concept

(1) penumbral tissue is an area of hypoperfused, abnormal tissue with physiological and biochemical characteristics, or both, consistent with cellular dysfunction but not cellular death;

(2) the tissue is within the same ischemic territory as the infarct core;

(3) the tissue can either survive or progress to necrosis; and (4) salvage of the tissue is associated with better clinical

outcome.

If it is not salvaged this tissue is progressively recruited into the infarct core which will expand with time into the maximal

volume originally at risk”Lancet 2009; 8: 261-69

Page 24: Stroke and neuroprotection

Neuronal protective agents

• Any agent or drug that protects the brain from secondary injury caused by stroke.

Page 25: Stroke and neuroprotection

NEUROPROTECTANTS

Hypothermia , powerful neuroprotective option but not well studied in stroke treatment

Nimodipine, several studies regarding nimodipine in stroke, with some confliciting results.

• NMDA receptor antagonists : e.g. : Dextrorphan, Selfotel (Higher mortality in selfotel group at 30 days (p<.05), and more behavioral effects, Stroke 2000;31(2):347-54)

• Nitric oxide synthetase inhibitor: e.g : Lubeluzole, poor efficacy as measured by barthel index, Stroke 1997;28:2338-2346

• Anti-adhesion antibodies : e.g. : Enlimomab (mortality and Rankin score worse in enlimomab administered patients, Neurology 1997;48(Supp) A270

• Above agents failed to show satisfactory results (serious adverse effects and lack of efficacy) except

• NEURONAL MEMBRANE STABILIZERS : Citicholine • FREE RADICAL SCAVENGERS : EDARAVONE

Page 26: Stroke and neuroprotection

Role of Edaravone in the management of Acute Ischaemic Stroke

Page 27: Stroke and neuroprotection

• Free radicals play crucial role in ischaemic brain injury

• Exacerbate membrane damage through peroxidation of unsaturated fatty acids leading to neuronal death and brain edema

• Physiological systems involved in removal of free radicals are impaired and formation of free radicals is further increased

Rationale for neuroprotection

Hiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006

Scavenging free radicals and prevention of lipid peroxidation can directly suppress

brain edema

Page 28: Stroke and neuroprotection

• Edaravone , a novel free radical scavenger protects neurons by inhibiting vascular endothelial injury and by ameliorating neuronal damage caused by brain edema

• Edaravone inhibits both nonenzymatic lipid peroxidation and lipooxygenase pathway

• Potent antioxidant effects against ischaemia/reperfusion-induced vascular endothelial cell injury, delays neuronal death, brain edema and consequently lessens the neurological deficits

Neuroprotection: Role of Edaravone

Hiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006

Page 29: Stroke and neuroprotection

Cerebral ischaemia Reperfusion

Excessive inflow of oxygen

H2O2

Deterioration of cerebral infarction with exacerbated symptoms

Increased infarct volume

Delayed neutrocytes necrosis

Neurological symptoms

Brain edema

Free radical production OH- Hydroxyl

Neurocyte injury

Cell membrane injury

Vascular endothelial injury

Activation of arachidonic cascade

Phospholipase A2

Free radical productionO2-(superoxide)

Adapted from Hiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006

Edaravone

Neuroprotection: Role of Edaravone

Page 30: Stroke and neuroprotection

• Edaravone can inhibit peroxidation of membrane lipids initiated by water soluble and lipid solouble radicals

• Edaravone is a low molecular wt radical scavenger which has a BBB permeability of 60% unlike Superoxide dismutase which has a difficulty in entering the BBB

• Edaravone, after administration eliminates highly toxic hydroxyl radicals, preferentially in ischemic penumbra

• Edaravone does not affect blood coagulation, platelet aggregation, fibrinolysis or bleeding time, hence there is no risk of additional bleeding

H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229

Neuroprotective effects of Edaravone in cerebrovascular injury

Page 31: Stroke and neuroprotection

Edaravone in acute brain infarction

A multicenter, randomized, placebo controlled, double blind trial conducted to verify its therapeutic efficacy in ischaemic stroke

N=250 (both thrombotic and embolic types), Edaravone - 125 patients; Placebo - 125 patients

Edaravone given within 72 hrs of onset of stroke at the dose of 30 mg, BID for 14 days

Fibrinolytic agents (urokinase, rtPA, ozagrel and citicoline) avoided throughout the study

H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229

Page 32: Stroke and neuroprotection

Edaravone in acute brain infarction

Functional outcome measured at 3 months or at discharge within three months using Modified Rankin Scale

Additionally outcome data collected at 3, 6 and 12 months Results – Significant difference between two groups in favour

of Edaravone group in terms of functional outcome (p=0.03) Improvement in functional outcome sustained for relatively

longer time Better clinical outcome when given within 24 hrs of symptom

onset

H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229

Page 33: Stroke and neuroprotection

Effect of novel free radical scavenger, edaravone on acute brain infarction

H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229

76

52

N=250 (both thrombotic and embolic types) ,edaravone (30 mg, BID for 14 days) given to 125 patients and placebo to 125

Edaravone : beneficial in combination therapy with fibrinolytic agents , leading to expansion of therapeutic time window

Page 34: Stroke and neuroprotection

Edaravone in internal carotid artery occlusion

Therapeutic effect of Edaravone was evaluated in patients with severe carotid artery stroke

Patients (baseline NIHSS score =/> 15) were treated with Edaravone for 14 days (n=30) and compared with historical control cohort of similar patients (n=31)*

Infarct volume on CT performed on day 2 in Edaravone group were smaller than those without Edaravone (p<0.02)

Hemorrhagic transformation of infarct on day 2 was less severe in Edaravone group compared to without it (p<0.03)

Kazunori Toyoda, Kenichiro Fujii,et al, Journal of the Neurological Sciences 221 (2004) 11-17

*10% Glycerol to all, rtPA, Heparin at discretion

Page 35: Stroke and neuroprotection

Edaravone in patients with internal carotid artery occlusion

Kazunori Toyoda, Kenichiro Fujii,et al, Journal of the Neurological Sciences 221 (2004) 11-17

Edaravone was associated with delayed evolution of infarcts and edema in patients with severe carotid artery stroke and decreased mortality during acute stage

Page 36: Stroke and neuroprotection

Effect of Edaravone on ischaemic cerebral edema assessed by MRI

T2-weigted MRI can both visualize and quantify vasogenic

edema therefore it is an important method to assess efficacy of therapies for stroke

Antiedema effect of Edaravone was evaluated in patients with extensive hemispheric ischaemic stroke

T2 relaxation time was calculated in the infarct core, boundary

zone of infarct and T2 mapping was performed before and after

edaravone treatment

Edaravone administration significantly decreased the mean T2 –

relaxation time in the boundary zone of infarct (p=0.008)

Conclusion – Edaravone can salvage the boundary zone of the infarct and is a useful cytoprotective antiedema agent

Satoshi Suda , Hironaka Igarashi, et al, Neurol. Med Chir (Tokyo) 47, 197-202,2007

Page 37: Stroke and neuroprotection

Edaravone diminishes free radicals from circulating neutrophils in patients with

ischaemic stroke

Study investigated effects of Edaravone on oxidative stress markers of circulating neutrophils in patients with ischaemic stroke

Edaravone 30mg – 21 patients; Ozagrel 40mg (thromboxane A2

synthase inhibitor) – 19 patients Intracellular reactive oxygen species of neutrophils were

measured by chemiluminescence assay Edaravone significantly decreased the intracellular reactive

oxygen species of neutrophils Conclusion – Reduction of intracellular reactive oxygen species

and suppression of superoxide production may be responsible for clinical efficacy of edaravone in patients with ischaemic stroke

Hitoshi Aizawa, Yoshiniro Makita, et al, Internal Medicine , doi:10.2169/internal medicine . 45.1491

Page 38: Stroke and neuroprotection

Efficacy of edaravone for the treatment of Acute Lacunar Infarction

Retrospective analysis of 70 patients with lacunar infarct admitted within 24 hrs of stroke onset, who were given Edaravone treatment in addition to routine treatment

Clinical status at baseline assessed using NIHSS score Modified Rankin Scale (MRS) used to assess clinical outcome at 3

months (good outcome defined as MRS =/<2) Routine treatment was continued (IV heparin, glycerol, ozagrel

sodium, oral antiplatelet drugs like aspirin, ticlopidine)

M. Mishira, Y. Komaba, et al , Neurol Med Chir (Tokyo) 45, 344-348, 2005

Page 39: Stroke and neuroprotection

Efficacy of edaravone for the treatment of Acute Lacunar Infarction

Edaravone added to conventional treatment (14 days) 70% of patients had a good outcome with MRS score =/<2 Higher baseline NIHSS score and higher age adversely

affected outcome After adjustment for this effect, the results still indicated that

Edaravone significantly improved functional outcome

M. Mishira, Y. Komaba, et al , Neurol Med Chir (Tokyo) 45, 344-348, 2005

Conclusion – Edaravone is a promising free radical scavenger for the treatment of patients with acute

lacunar stroke

Page 40: Stroke and neuroprotection

Edaravone in patients with traumatic brain injury (TBI)

Lipid peroxidation caused by reactive oxygen species is involved in traumatic brain injury (TBI)

Therapeutic strategy for TBI involves control of lipid peroxidation

Present study used in vitro & ex vivo techniques to study whether Edaravone can scavenge alkoxyl radicals (OR-)

Jugular venous blood collected from 17 TBI patients immediately before and 20 min after Edaravone administration

Keneji Dohi, Kazue satoh, et al, Journal of Neurotrauma, Volume 23, Number 11, 2006, pp. 1591-1599

Page 41: Stroke and neuroprotection

Higher OR- levels in blood of untreated patients than in normal control

Treatment with edaravone suppresses OR- level by 24.6%

Conclusion – Edaravone may be useful for preventing lipid peroxidation in patients with TBI

Keneji Dohi, Kazue satoh, et al, Journal of Neurotrauma, Volume 23, Number 11, 2006, pp. 1591-1599

Edaravone in patients with traumatic brain injury (TBI)

Page 42: Stroke and neuroprotection

Diminishes Free Radicals from Circulating Neutrophils in Ischemic Brain Attack

Amount of superoxide produced by neutrophils stimulated byphorbol myristate acetat (PMA) before and after treatmentwith edaravone or ozagrel

The superoxideproduction by neutrophils decreased after treatment with edaravone in patients with ischemic brain attack (Wilcoxontest, p=0.001)

2006 The Japanese Society of Internal Medicine

Page 43: Stroke and neuroprotection

IV Inj. Edaravone 30 mg for 10 min before myocardial reperfusion decreasedSerum CK-MB and improved left ventricular ejection fraction in pts with

Acute MI

Edaravone in Acute Myocardial Infarct

Recent Patents on Cardiovascular Drug Discovery, 2006, Vol. 1, No. 1 89

Page 44: Stroke and neuroprotection

Clinical Evidence in CEA

• Pretreatment with edaravone can prevent development of cognitive impairment after carotid endarterectomy (CEA). |Surg Neurol. 2005 Oct;64(4):309-13

• In patients with cortical infarcts, edaravone reduced oxidative damage, thereby limiting the degree of brain damage, as measured by plasma biomarkers. Free Radic Biol Med. 2005 Oct 15;39(8):1109-16.

Page 45: Stroke and neuroprotection

Edaravone – new clinical data

• Edaravone dose-dependently increases rehabilitation gain according to DeltaFIM-

M and DeltaBI scores in patients with cardioembolic stroke. Clin Drug Investig.

2010;30(3):143-55

• Edaravone significantly reduced oxidative cell death in both neuronal cells and

primary rat astrocytes and thus protects component of neurovascular unit. Brain

Res. 2010 Jan 11;1307:22-7

• Edaravone inhibited production of free radicals known to induce neuronal

degeneration and cell death after brain injury, with the potential to differentiate

into neurons and glia around the area damaged by TBI. Neurotox Res. 2009

Nov;16(4):378-89.

Page 46: Stroke and neuroprotection

Citicoline in Stroke

Page 47: Stroke and neuroprotection

Rationale for citicoline

• Precursor of phosphatidylcholine, a vital component of neuronal membrane.

• Reduces the dysfunction of BBB, decreases cerebral edema, activates cerebral energy metabolism.

• Provides the cytidine & choline. Choline is essential for the synthesis of Acetylcholine (the cholinergic neurotransmitter)

• Inhibits Phospholipase A2 thereby :– preserves neuronal membrane integrity– promotes neuronal membrane repair– inhibits the release of free fatty acids & ARA – inhibits free radical damage

J our Of Neurochemistry, 2002,80,12-23

Jour Of NeuroSci Res, 2002, 70:133-9

Page 48: Stroke and neuroprotection

Effect of citicoline

A. Normal synthesis of phophotidylcholine

B. Effect of Ischemia

C. Reversal of increased FFA with citicoline

Page 49: Stroke and neuroprotection

Clinical efficacy

Since 1980’s , 13 trials have been done with citicoline in stroke management

9 in Europe & Japan, 4 in the U.S. European trials showed citicoline improved global & neurological

function , earlier motor & cognitive recovery Large multicenter studies in Japan showed citicoline improved global

outcome rating scale However, subsequent analysis showed citicoline treatment for 6

weeks improved overall recovery at week 12

Page 50: Stroke and neuroprotection

A comparative, randomized study evaluated efficacy of citicoline N = 80 (>65 years, in acute phase of ischemic stroke) Mild to moderate impaired consciousness with a score of >10 on GCS

(Glasgow coma scale) Equal no. of patients received citicoline & control Dose – Citicoline 1g/8hrs as a daily dose for 10 days Citicoline showed significant improvement in GCS score (12.55 to 13.85)

Citicoline in acute cerebrovascular disease

    

    

Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006 Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1

.

Page 51: Stroke and neuroprotection

(Significant improvement in GCS scores)

Citicoline in acute cerebrovascular disease

Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006 Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1.

Page 52: Stroke and neuroprotection

Significant decrease in lesion volume by 17.2 cc compared to placebo by 6.9 cc at 12 weeks as measured by MRI.

Placebo citicoline

Citicoline in acute cerebrovascular disease

N=100 Citicoline 500mg/day (oral) for 6 weeks.

Expert Opinion on Pharmacotherapy, Volume 10, Number 5, April 2009 , pp. 839-846(8)

Page 53: Stroke and neuroprotection

Citicoline in HEAD INJURY

• Accelerates the recovery of neurological symptoms

• Accelerates the resolution of brain edema on CT

• Reduces hospital stay

• Better quality in the evolution

• Improves the global functional outcome

• Reduces the post-concussional syndrome

Page 54: Stroke and neuroprotection

Citicoline in head trauma

A double blind ,placebo controlled study involving 60 patients with severs head trauma

Citicoline 750mg/day (IV) – 6 days Citicoline 750mg/day (IM) – 20 days Clinical evaluation was continued for upto 6 months.

Observations Response to painful stimuli superior in citicoline group at

day 15 compared to placebo (p<0.01) Greater recovery from neurological deficits observed in

citicoline group Autonomous ambulation was seen in 84% of patients in

citicoline grp compared to 62.5 in placebo at 120 days Difference statistically significant from day 60 (p<0.01)

Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006 Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1.

Page 55: Stroke and neuroprotection

(Number of patients showing normalization of state of consciousness in relation to time and treatment)

Citicoline in head trauma

N=100 p=<0.05

Response to painful stimuli superior in citicoline group at day 15 Greater recovery from neurological deficits and Autonomous ambulation was seen in 84% of patients in citicoline grp

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(Significantly less % of patients showing neurological complications with citicoline

Citicoline in head trauma

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Clinical data –citicoline in stroke

In a double blind, multicenter (63 Japanese Academic centers),

placebo controlled study in 272 patients with stroke given citicoline

1g/day/14 days (IV) -- effective and safe drug for the treatment of

acute cerebral infarction. (Stroke. 1988;19:211-216)

• A multicenter, DB controlled trial, conducted by the Citicoline Stroke

Study Group (N=259) examined the effects of oral citicoline(500mg;

1,000 mg; or 2,000 mg) after 12 weeks showed that citicoline pts

have twice the chance of stroke recovery compared to patients on

placebo. (Neurology 1997;49:671-78)

Page 59: Stroke and neuroprotection

Clinical data –citicoline in stroke

Meta-analysis of 4 large trial done in the U.S.-- citicoline

treatment showed significant improvement in patients who

had achieved an almost complete recovery at 3 months in

daily routine activity and functional activity and is more

effective in patients with moderate to severe acute ischaemic

stroke (Stroke. 2002;33:2850-2857)

• Similarly citicoline found effective if combined with

thromlytic agents in stroke .

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Citicoline –New data

• Citicoline in Stroke – citicoline administered within 24h after

moderate to severe stroke is safe and increases the probability of recovery within 3 months- Exp Opin Pharmthr Apr 2009

• Citicoline in Brain Injury CORBIT Trial – Ongoing to complete enrollment by Aug 2010 - J Neurotrauma Dec 2009

• Citicoline widely available agent in Neuroprotection and repair –Meta-analysis of 10 trials enrolling 2279 pts suggests citicoline treatment reduced frequency of death and disability. (Rev Neurol Dis 2008)

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Citicoline in Mild Cognitive Impairment

Mild cognitive impairment (MCI) involves slight loss of memory without significant effect on other cognitive functions

Approximately 12% of patients with MCI advance annually to develop Alzheimer’s disease

Meta analysis of 12 clinical trials show Citicoline improves memory Behavior Overall clinical improvement

Hence citicoline may prove effective in age related cognitive decline that may be a precursor of dementia

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Citicoline in Parkinson’s disease

Citicoline shown dopamine agonist properties

Citicoline 600mg/day/10 days (IV) shown improvement in bradykinesia, rigidity & tremors

Allows reduction of levodopa ,hence reduces levodopa related adverse effects

Discontinuation of citicoline worsened symptoms

• New strategies in the management of Parkinson’s disease using a phospholipid precursor (CDP-choline) improvements in bradykinesia and rigidity.

(Neuropsychobiology 1982;8:289-296.)

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Thank You